Beta-hemoglobinopathies are diseases characterized by defective or insufficient expression of the beta-chain of adult hemoglobin, and lead to the anemia associated with sickle cell disease (SCD) and beta-thalassemia. One approach to treat beta-hemoglobinopathies, and in particular SCD, involves the elevation of fetal hemoglobin (HbF) expression in patients. The rationale for this approach came from observations that patients with SCD that also harbor secondary genetic mutations for persistent HbF expression into adulthood exhibit reduced pathophysiological symptoms associated with SCD. Hydroxyurea (HU) is currently the only FDA-approved therapy for SCD and reduces the number of clinical crisis and incidence of episodic pain. However, the use of HU therapy is hindered by dose-limiting toxicity and poor response rate of many patients with SCD, highlighting an unmet medical need for better therapeutic options to treat this disease. The work proposed within this application leverages FibroGen's technology platform aimed at therapeutic HIF stabilization, and in our anemia program we have developed a series of orally bioavailable HIF prolyl hydroxylases inhibitors (PHI) that elevate circulating, endogenous EPO levels and potently stimulate erythropoiesis with repeated intermittent dosing. In the phase I SBIR program, we demonstrated that erythropoietic PHI are also capable of inducing HbF in human bone marrow-derived CD34+ cells undergoing erythroid expansion ex vivo. The primary goal of the proposed phase 2 SBIR plan is to obtain proof-of- concept that orally bioavailable, erythropoietic PHI can elevate HbF protein expression in anemic non-human primates, either alone or in combination with HU. Enhancing HbF expression is long recognized as an important protective mechanism against SCD. The ability to activate the HbF expression program by PHI may prove to be a powerful approach in the therapeutic treatment of SCD and beta-hemoglobinopathies.